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EP3122707B1 - Procédé de couplage d'un premier composé aromatique à un second composé aromatique - Google Patents

Procédé de couplage d'un premier composé aromatique à un second composé aromatique Download PDF

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Publication number
EP3122707B1
EP3122707B1 EP15716307.2A EP15716307A EP3122707B1 EP 3122707 B1 EP3122707 B1 EP 3122707B1 EP 15716307 A EP15716307 A EP 15716307A EP 3122707 B1 EP3122707 B1 EP 3122707B1
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Prior art keywords
aromatic compound
palladium
bis
substituted
yield
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German (de)
English (en)
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EP3122707A1 (fr
Inventor
Patrick S. HANLEY
Gregory T. Whiteker
Matthias S. Ober
William J. Kruper Jr.
Arkady L. Krasovskiy
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Dow Global Technologies LLC
Corteva Agriscience LLC
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Dow AgroSciences LLC
Dow Global Technologies LLC
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
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    • C07C2531/28—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups C07C2531/02 - C07C2531/24 of the platinum group metals, iron group metals or copper

Definitions

  • Suzuki-Miyaura coupling is a valuable synthetic method for coupling a first aromatic compound to a second aromatic compound, thereby forming a new carbon-carbon bond between the aromatic compounds.
  • the first aromatic compound is substituted by a halide.
  • the first aromatic compound used in the Suzuki coupling is prepared from an aromatic compound having a hydroxyl substituent.
  • the second aromatic compound includes a boron-containing substituent.
  • triflates having the formula F 3 CSO 2 -
  • the expense of triflic anhydride (CF 3 SO 2 ) 2 O has limited the use of triflates in Suzuki couplings to the production of fine chemicals.
  • the atom economy of triflic anhydride is low since half of the molecule is expended as monomeric triflate anion (CF 3 SO 2 - ) following functionalization of a phenolic precursor.
  • Suzuki coupling reactions involving triflates exhibit sensitivity to water under basic conditions.
  • aryl methanesulfonates are suitable for aryl-aryl cross-coupling reactions.
  • One drawback of aryl-aryl cross-couping using aryl methanesulfonates is that these reactions require expensive palladium catalysts.
  • Another drawback of aryl-aryl cross-coupling using aryl methanesulfonates is low atom economy.
  • US 2001/0020104 discloses a process for preparing substituted benzyl compounds and toluene derivatives.
  • WO 2014/031791 discloses methods of preparing aromatic compounds.
  • numeric ranges for instance "from 2 to 10,” are inclusive of the numbers defining the range (e.g., 2 and 10).
  • ratios, percentages, parts, and the like are by weight.
  • molecular weight refers to the number average molecular weight as measured in conventional manner.
  • Alkyl as used in this specification, whether alone or as part of another group (e.g., in dialkylamino), encompasses straight and branched chain aliphatic groups having the indicated number of carbon atoms. If no number is indicated (e.g., aryl-alkyl-), then 1-12 alkyl carbons are contemplated.
  • Preferred alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and tert-octyl.
  • heteroalkyl refers to an alkyl group as defined above with one or more heteroatoms (nitrogen, oxygen, sulfur, phosphorus) replacing one or more carbon atoms within the radical, for example, an ether or a thioether.
  • aryl refers to any functional group or substituent derived from an aromatic ring.
  • aryl refers to an aromatic moiety comprising one or more aromatic rings.
  • the aryl group is a C 6 -C 18 aryl group.
  • the aryl group is a C 6 -C 10 aryl group.
  • the aryl group is a C 10 -C 18 aryl group.
  • Aryl groups contain 4n+2 pi electrons, where n is an integer.
  • the aryl ring may be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings or heterocycloalkyl rings.
  • Preferred aryls include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl. Unless otherwise indicated, the aryl group is optionally substituted with 1 or more substituents that are compatible with the syntheses described herein. Such substituents include, but are not limited to, sulfonate groups, boron-containing groups, alkyl groups, nitro groups, halogens, cyano groups, carboxylic acids, esters, amides, C 2 -C 8 alkene, and other aromatic groups. Other substituents are known in the art. Unless otherwise indicated, the foregoing substituent groups are not themselves further substituted.
  • Heteroaryl refers to any functional group or substituent derived from an aromatic ring and containing at least one heteroatom selected from nitrogen, oxygen, and sulfur.
  • the heteroaryl group is a five or six-membered ring.
  • the heteroaryl ring may be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings or heterocycloalkyl rings.
  • heteroaryl groups include, without limitation, pyridine, pyrimidine, pyridazine, pyrrole, triazine, imidazole, triazole, furan, thiophene, oxazole, thiazole.
  • the heteroaryl group may be optionally substituted with one or more substituents that are compatible with the syntheses described herein.
  • substituents include, but are not limited to, fluorosulfonate groups, boron-containing groups, C 1 -C 8 alkyl groups, nitro groups, halogens, cyano groups, carboxylic acids, esters, amides, C 2 -C 8 alkene and other aromatic groups.
  • Other substituents are known in the art. Unless otherwise indicated, the foregoing substituent groups are not themselves further substituted.
  • Aromatic compound refers to a ring system having 4n+2 pi electrons where n is an integer.
  • the present disclosure describes a process for coupling a first aromatic compound to a second aromatic compound.
  • This process is shown generally in Equation 1, whereby a first aromatic compound having a hydroxyl group is first reacted with SO 2 F 2 and a base and is second reacted with a second aromatic compound having a boron-containing substituent in the presence of a catalyst.
  • the hydroxyl group could be deprotonated to form a phenolate (e.g. the deprotonation step could be performed prior to introduction of A 1 to the reaction mixture or after the introduction to the reaction mixture).
  • the reaction of Equation 1 may be performed as a one-pot reaction, as compared to performing the reaction indiscrete steps. Without being limited by theory, it is anticipated that the reaction shown in Equation 1 proceeds along the same reaction path whether performed as a one-pot reaction or as discrete steps.
  • the first step comprises reacting a first aromatic compound having a hydroxyl substituent with SO 2 F 2 to yield the product shown in Equation 2
  • the second step comprises reacting the product of Equation 2 with a second aromatic compound having a boron-containing substituent to yield the product shown in Equation 3.
  • the process involves a one-pot reaction where a first aromatic compound having a hydroxyl group is first reacted with SO 2 F 2 and a base and is second reacted with a second aromatic compound having a boron-containing substituent in the presence of a catalyst, as shown generally in Equation 1.
  • Equation 3 is the same general reaction as depicted by step 2) of the reaction shown in Equation 1.
  • Equation 1 the first aromatic compound is identified as A 1 and the second aromatic compound is identified as A 2 .
  • the first aromatic compound is either an aryl group or a heteroaryl group.
  • the second aromatic compound is either an aryl group or a heteroaryl group.
  • the result of the reactions shown in Equation 3 and Equation 3 is the formation of a new carbon-carbon bond between the first aromatic compound and the second aromatic compound, thereby coupling the first aromatic compound to the second aromatic compound.
  • the first aromatic compound is bonded to a fluorosulfonate group.
  • a fluorosulfonate group refers to O-fluorosulfonate of the formula -OSO 2 F.
  • O-fluorosulfonate may be synthesized from sulfuryl fluoride.
  • the fluorosulfonate group serves as a leaving group from the first aromatic compound.
  • the sulfuryl atom of the fluorosulfonate group is bonded to the oxygen of the hydroxyl group of the first aromatic compound.
  • the second aromatic compound includes a boron-containing substituent as identified in Equation 1 and Equation 3 as B x .
  • the boron-containing substituent is of the formula -BF 3 - M + where M + is an alkali metal cation or an unsubstituted ammonium ion.
  • the boron of the boron-containing substituent has one or more alkyl substituent, for example, 9-borabicyclo[3.3.1]nonane.
  • the boron-containing substituent is of the formula shown in Equation 4.
  • R 1 and R 2 are each independently C 1-18 alkyl, C 3-18 cycloalkyl, C 6-18 aryl, or H.
  • R 1 and R 2 are covalently linked to each other to form a ring that includes -R 1 -O-B-O-R 2 -.
  • one or more of R 1 and R 2 are boron, for example, in a boroxane. Boron-containing substituents which are known to be suitable for typical Suzuki reactions are suitable here.
  • the first aromatic compound is reacted with the second aromatic compound in a reaction mixture.
  • the reaction mixture includes a catalyst having at least one group 10 atom.
  • the reaction mixture also includes a ligand, and a base.
  • the group 10 atoms include nickel, palladium and platinum.
  • the catalyst is provided in a form suitable to the reaction conditions.
  • the catalyst is provided on a substrate.
  • the catalyst having at least one group 10 atom is generated in situ from one or more precatalysts and one or more ligands.
  • palladium precatalysts examples include, but are not limited to, Palladium(II) acetate, Palladium(II) chloride, Dichlorobis(acetonitrile)palladium(II), Dichlorobis(benzonitrile)palladium(II), Allylpalladium chloride dimer, Palladium(II) acetylacetonate, Palladium(II) bromideBis(dibenzylideneacetone)palladium(0), Bis(2-methylallyl)palladium chloride dimer, Crotylpalladium chloride dimer, Dichloro(1,5-cyclooctadiene)palladium(II), Dichloro(norbornadiene)palladium(II), Palladium(II) trifluoroacetate, Palladium(II) benzoate, Palladium(II) trimethylacetate, Palladium(II) oxide, Palladium(II) cyanide
  • nickel-based catalysts are used.
  • platinum-based catalysts are used.
  • a catalyst including one or more of nickel, platinum and palladium -based catalysts are used.
  • pyridine-enhanced precatalyst preparation stabilization and initiation (PEPPSI) type catalysts are used, for example, [1,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride, and (1,3-Bis(2,6-diisopropylphenyl) imidazolidene) (3-chloropyridyl) palladium(II) dichloride.
  • nickel precatalysts include, but are not limited to, nickel(II) acetate, nickel(II) chloride, Bis(triphenylphosphine)nickel(II) dichloride, Bis(tricyclohexylphosphine) nickel(II) dichloride, [1,1'-Bis(diphenylphosphino)ferrocene]dichloronickel(II), Dichloro[1,2-bis(diethylphosphino)ethane]nickel(II), Chloro(1-naphthyl)bis(triphenylphosphine)nickel(II), 1,3-Bis(2,6-diisopropylphenyl)imidazolium chloride, Bis(1,5-cyclooctadiene)nickel(0), Nickel(II) chloride ethylene glycol dimethyl ether complex, [1,3-Bis(diphenylphosphino) propane]dichloronickel(
  • the ligand used in the reaction mixture is preferably selected to generate the selected catalyst from a pre-catalyst.
  • the ligand may be a phosphine ligand, a carbene ligand, an amine-based ligand, a carboxylate based ligand, an aminodextran, an aminophosphine-based ligands or an N-heterocyclic carbene-based ligand.
  • the ligand is monodentate.
  • the ligand is bidentate.
  • the ligand is polydentate.
  • Suitable phosphine ligands may include, but are not limited to, mono- and bi-dentate phosphines containing functionalized aryl or alkyl substituents or their salts.
  • suitable phosphine ligands include, but are not limited to, triphenylphosphine; Tri( o- tolyl)phosphine; Tris(4-methoxyphenyl)phosphine; Tris(pentafluorophenyl)phosphine; Tri( p- tolyl)phosphine; Tri(2-furyl)phosphine; Tris(4-chlorophenyl)phosphine; Di(1-adamantyl)(1-naphthoyl)phosphine; Benzyldiphenylphosphine; 1,1'-Bis(di-t-butylphosphino)ferrocene; (-)-1,2-Bis((2R,5R)
  • Suitable amine and aminophosphine-based ligands include any combination of monodentate or bidentate alkyl and aromatic amines including, but not limited to, pyridine, 2,2'-Bipyridyl, 4,4'-Dimethyl-2,2'-dipyridyl, 1,10-Phenanthroline, 3,4,7,8-Tetramethyl-1,10-phenanthroline, 4,7-Dimethoxy-1,10-phenanthroline, N,N,N',N' -Tetramethylethylenediamine, 1,3-Diaminopropane, ammonia, 4-(Aminomethyl)pyridine, (1 R ,2 S ,9 S ) -(+)-11-Methyl-7,11-diazatricyclo[7.3.1.0 2,7 ]tridecane, 2,6-Di- tert -butylpyridine, 2,2'-Bis[(4 S )-4-benzyl-2-oxazoline], 2,2-B
  • aminophosphine ligands such as 2-(Diphenylphosphino)ethylamine, 2-(2-(Diphenylphosphino)ethyl)pyridine, (1R,2R)-2-(diphenylphosphino)cyclohexanamine, an aminodextran and 2-(Di- tert- butylphosphino)ethylamine.
  • Suitable carbene ligands include N-heterocyclic carbene (NHC) based ligands, including, but not limited to, 1,3-Bis(2,4,6-trimethylphenyl)imidazolinium chloride, 1,3-Bis(2,6-diisopropylphenyl)imidazolium chloride, 1,3-Bis-(2,6-diisopropylphenyl) imidazolinium chloride, 1,3-Diisopropylimidazolium chloride, and 1,3-Dicyclohexylbenzimidazolium chloride.
  • N-heterocyclic carbene (NHC) based ligands including, but not limited to, 1,3-Bis(2,4,6-trimethylphenyl)imidazolinium chloride, 1,3-Bis(2,6-diisopropylphenyl)imidazolium chloride, 1,3-Bis-(2,6-diisopropylphen
  • the base used in the reaction mixture is selected to be compatible with the catalyst, the boron-containing substituent and the fluorosulfonate.
  • Suitable bases include, but are not limited to, carbonate salts, phosphate salts, acetate salts and carboxylic acid salts. Unexpectedly, it has been found that inorganic bases are suitable in the reaction mixture.
  • Examples of carbonate salts include, but are not limited to, lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, ammonium carbonate, substituted ammonium carbonates, and the corresponding hydrogen carbonate salts.
  • Examples of phosphate salts include, but are not limited to, lithium phosphate, sodium phosphate, potassium phosphate, rubidium phosphate, cesium phosphate, ammonium phosphate, substituted ammonium phosphates, and the corresponding hydrogen phosphate salts.
  • Examples of acetate salts include, but are not limited to, lithium acetate, sodium acetate, potassium acetate, rubidium acetate, cesium acetate, ammonium acetate, and substituted ammonium acetates.
  • bases include, but are not limited to, salts of formate, fluoroacetate, and propionate anions with lithium, sodium, potassium, rubidium, cesium, ammonium, and substituted ammonium cations; metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, metal dihydroxides such as magnesium dihydroxide, calcium dihydroxide, strontium dihydroxide, and barium dihydroxide; metal trihydroxides such as aluminum trihydroxide, gallium trihydroxide, indium trihydroxide, thallium trihydroxide; non nucleophilic organic amines such as triethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-Diazabicyclo[4.3.0] non-5-ene (DBN), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU); bis(s
  • amine bases such as alkylamines and heteroarenes
  • examples of amine bases include, but are not limited to, triethylamine, pyridine, morpholine, 2,6-lutidine, triethylamine, N,N-Dicyclohexylmethylamine, and diisopropylamine.
  • the base is used in the presence of a phase-transfer catalyst. In another instance, the base is used in the presence of water. In yet another instance, the base is used in the presence of an organic solvent. In still another instance, the base is used in the presence of one or more of a phase-transfer catalyst, water or an organic solvent.
  • At least one equivalent of base is present for each equivalent of fluorosulfonate. In some embodiments, no more than 10 equivalents of base are present for each equivalent of fluorosulfonate. In some embodiments, at least 2 equivalents of base are present for each equivalent of fluorosulfonate. In some embodiments, no more than 6 equivalents of base are present for each equivalent of fluorosulfonate.
  • the solvent in the reaction mixture is selected such that it is suitable for use with the reactants, the catalyst, the ligand and the base.
  • suitable solvents include toluene, xylenes ( ortho -xylene, meta -xylene, para -xylene or mixtures thereof), benzene, water, methanol, ethanol, 1-propanol, 2-propanol, n -butanol, 2-butanol, pentanol, hexanol, tert -butyl alcohol, tert -amyl alcohol, ethylene glycol, 1,2-propanedioal, 1,3-propanediol, glycerol, N -methyl-2-pyrrolidone, acetonitrile, N,N -dimethylformamide, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, triacetin, acetone, methyl e
  • the solvent includes any combination of the solvents described herein, in, or in the absence of, a surfactant.
  • the sulfuryl fluoride is used neat at a sufficiently low temperature that the sulfuryl fluoride is in a liquid.
  • reaction mixture water is included in the reaction mixture.
  • fluorosulfonates as compared to triflates, is that the reaction can be carried out without a subsequent separation step, or with a simple separation step.
  • a dedicated purification step is required to remove byproducts since the products and the byproducts typically occupy the same phase.
  • the byproducts are either in the gas phase, and will bubble out spontaneously or with a simple degassing step, or will partition into the aqueous phase, which is easily separable.
  • the reaction scheme described herein provides additional benefits as compared to Suzuki couplings involving triflates.
  • the reaction described herein is completed as a one-pot reaction as shown in Equation 1.
  • a first step an aromatic compound having an alcohol substituent is added to a reaction mixture in the presence of sulfuryl fluoride and a base.
  • the base may be any of the bases described herein, including, without limitation, amine bases and inorganic bases.
  • This first step couples the fluorosulfonate substituent to the oxygen of the hydroxyl group.
  • a second aromatic compound having a boron-containing substituent and a catalyst may be a suitable group 10 catalyst, including, without limitation, platinum, palladium and nickel catalysts.
  • the product of this second step is a bi-aryl compound formed by coupling the first aromatic compound and the second aromatic compound.
  • the reaction mixture in each vial is heated to 80°C for 17 hours with vigorous stirring. Following heating, the reaction mixture in each vial is cooled to room temperature, and thereafter 5 mL of trimethoxybenzene in ethyl acetate (1.33 M solution) is added to the reaction mixture in each vial and each vial is shaken. An aliquot from the organic layer of the reaction mixture of each vial is analyzed by gas chromatography, and the yield of 4-phenyltoluene is determined from the integration of the 4-phenyltoluene peak compared to that of the integration of the trimethoxybenzene peak, with a correction factor of 1.55. The yield of 4-phenyltoluene for each vial is listed in Table 6.
  • vial C A third 20 mL scintillation vial (“vial C") is charged with 22.5 mg of 0.1 mmol palladium acetate, 80.7 mg of 0.2 mmol CMPhos, and 1 mL of 1,4-dioxane. 279 ⁇ L of 2.0 mmol triethylamine and 200 ⁇ L of the solution of vial C are pippeted to vial A.
  • vial D A fourth 20 mL scintillation vial (“vial D") is charged with 22.5 mg of 0.1 mmol palladium acetate, 52.5 mg of 0.2 mmol PPh 3 and 1 mL of 1,4-dioxane. 279 ⁇ L of 2.0 mmol triethylamine and 200 ⁇ L of the solution of vial D is pippeted to vial B.
  • Vials A and B are stirred at 80 °C for 17 hours.
  • 1 mL of brine and 2 mL of ethyl acetate are added to each of vials A and B.
  • the organic layers of each vial are separated via pipette.
  • the aqueous layer of each vial is extracted several times with ethyl acetate.
  • the remaining organic layers of each vial are extracted and combined with the respective previously-separated organic layer.
  • Each organic layer is brought to a total weight of 10.00 g by the addition of ethyl acetate.
  • the two reactions are individually worked up by addition of 1 mL brine and 2 mL ethyl acetate and separation of the organic layer via pipette.
  • the aqueous layer is extracted several times with ethyl acetate and the combined organic phases are each brought to a total weight of exactly 10.00 g by addition of ethyl acetate.
  • the remaining 9.00 g organic phase of the CMPhos catalyzed reaction is concentrated and purified by automated flash chromatography (dry loading onto silica loading cartridge, 24g Grace normal phase silica purification cartridge, isocratic hexanes).
  • the product elutes as a single peak and is isolated by evaporation of the solvent followed by drying under high vacuum.
  • vial C A third 20 mL scintillation vial (“vial C") is charged with 22.5 mg of 0.1 mmol palladium acetate, 80.7 mg of 0.2 mmol CMPhos, and 1 mL of 1,4-dioxane. 279 ⁇ L of 2.0 mmol triethylamine and 200 ⁇ L of the solution of vial C are pippeted to vial A.
  • vial D A fourth 20 mL scintillation vial (“vial D") is charged with 22.5 mg of 0.1 mmol palladium acetate, 52.5 mg of 0.2 mmol PPh 3 and 1 mL of 1,4-dioxane. 279 ⁇ L of 2.0 mmol triethylamine and 200 ⁇ L of the solution of vial D is pippeted to vial B.
  • Vials A and B are stirred at 80 °C for 17 hours.
  • 1 mL of brine and 2 mL of ethyl acetate are added to each of vials A and B.
  • the organic layers of each vial are separated via pipette.
  • the aqueous layer of each vial is extracted several times with ethyl acetate.
  • the remaining organic layers of each vial are extracted and combined with the respective previously-separated organic layer.
  • Each organic layer is brought to a total weight of 10.00 g by the addition of ethyl acetate.
  • the two reactions are individually worked up by addition of 1 mL brine and 2 mL ethyl acetate and separation of the organic layer via pipette.
  • the aqueous layer is extracted several times with ethyl acetate and the combined organic phases are each brought to a total weight of exactly 10.00 g by addition of ethyl acetate.
  • the remaining 9.00 g organic phase of the CMPhos catalyzed reaction is concentrated and purified by automated flash chromatography (dry loading onto silica loading cartridge, 24g Grace normal phase silica purification cartridge, isocratic hexanes).
  • the product elutes as a single peak and is isolated by evaporation of the solvent followed by drying under high vacuum.
  • vial C A third 20 mL scintillation vial (“vial C") is charged with 22.5 mg of 0.1 mmol palladium acetate, 80.7 mg of 0.2 mmol CMPhos, and 1 mL of 1,4-dioxane. 279 ⁇ L of 2.0 mmol triethylamine and 200 ⁇ L of the solution of vial C are pippeted to vial A.
  • vial D A fourth 20 mL scintillation vial (“vial D") is charged with 22.5 mg of 0.1 mmol palladium acetate, 52.5 mg of 0.2 mmol PPh 3 and 1 mL of 1,4-dioxane. 279 ⁇ L of 2.0 mmol triethylamine and 200 ⁇ L of the solution of vial D is pippeted to vial B.
  • Vials A and B are stirred at 80 °C for 17 hours.
  • 1 mL of brine and 2 mL of ethyl acetate are added to each of vials A and B.
  • the organic layers of each vial are separated via pipette.
  • the aqueous layer of each vial is extracted several times with ethyl acetate.
  • the remaining organic layers of each vial is extracted and combined with the respective previously-separated organic layer.
  • Each organic layer is brought to a total weight of 10.00 g by the addition of ethyl acetate.
  • the two reactions are individually worked up by addition of 1 mL brine and 2 mL ethyl acetate and separation of the organic layer via pipette.
  • the aqueous layer is extracted several times with ethyl acetate and the combined organic phases are each brought to a total weight of exactly 10.00 g by addition of ethyl acetate.
  • the remaining 9.00 g organic phase of the CMPhos catalyzed reaction is concentrated and purified by automated flash chromatography (dry loading onto silica loading cartridge, 24g Grace normal phase silica purification cartridge, isocratic hexanes).
  • the product elutes as a single peak and is isolated by evaporation of the solvent followed by drying under high vacuum.
  • vial C A third 20 mL scintillation vial (“vial C") is charged with 22.5 mg of 0.1 mmol palladium acetate, 80.7 mg of 0.2 mmol CMPhos, and 1 mL of 1,4-dioxane. 279 ⁇ L of 2.0 mmol triethylamine and 200 ⁇ L of the solution of vial C are pippeted to vial A.
  • vial D A fourth 20 mL scintillation vial (“vial D") is charged with 22.5 mg of 0.1 mmol palladium acetate, 52.5 mg of 0.2 mmol PPh 3 and 1 mL of 1,4-dioxane. 279 ⁇ L of 2.0 mmol triethylamine and 200 ⁇ L of the solution of vial D is pippeted to vial B.
  • Vials A and B are stirred at 80 °C for 17 hours.
  • 1 mL of brine and 2 mL of ethyl acetate are added to each of vials A and B.
  • the organic layers of each vial are separated via pipette.
  • the aqueous layer of each vial is extracted several times with ethyl acetate.
  • the remaining organic layers of each vial are extracted and combined with the respective previously-separated organic layer.
  • Each organic layer is brought to a total weight of 10.00 g by the addition of ethyl acetate.
  • the two reactions are individually worked up by addition of 1 mL brine and 2 mL ethyl acetate and separation of the organic layer via pipette.
  • the aqueous layer is extracted several times with ethyl acetate and the combined organic phases are each brought to a total weight of exactly 10.00 g by addition of ethyl acetate.
  • the remaining 9.00 g organic phase of the CMPhos catalyzed reaction is concentrated and purified by automated flash chromatography (dry loading onto silica loading cartridge, 24g Grace normal phase silica purification cartridge, isocratic hexanes).
  • the product elutes as a single peak and is isolated by evaporation of the solvent followed by drying under high vacuum.
  • vial C A third 20 mL scintillation vial (“vial C") is charged with 22.5 mg of 0.1 mmol palladium acetate, 80.7 mg of 0.2 mmol CMPhos, and 1 mL of 1,4-dioxane. 279 ⁇ L of 2.0 mmol triethylamine and 200 ⁇ L of the solution of vial C are pippeted to vial A.
  • vial D A fourth 20 mL scintillation vial (“vial D") is charged with 22.5 mg of 0.1 mmol palladium acetate, 52.5 mg of 0.2 mmol PPh 3 and 1 mL of 1,4-dioxane. 279 ⁇ L of 2.0 mmol triethylamine and 200 ⁇ L of the solution of vial D is pippeted to vial B.
  • Vials A and B are stirred at 80 °C for 17 hours.
  • 1 mL of brine and 2 mL of ethyl acetate are added to each of vials A and B.
  • the organic layers of each vial are separated via pipette.
  • the aqueous layer of each vial is extracted several times with ethyl acetate.
  • the remaining organic layers of each vial are extracted and combined with the respective previously-separated organic layer.
  • Each organic layer was brought to a total weight of 10.00 g by the addition of ethyl acetate.
  • the two reactions are individually worked up by addition of 1 mL brine and 2 mL ethyl acetate and separation of the organic layer via pipette.
  • the aqueous layer is extracted several times with ethyl acetate and the combined organic phases are each brought to a total weight of exactly 10.00 g by addition of ethyl acetate.
  • the remaining 9.00 g organic phase of the CMPhos catalyzed reaction is concentrated and purified by automated flash chromatography (dry loading onto silica loading cartridge, 24g Grace normal phase silica purification cartridge, isocratic hexanes).
  • the product elutes as a single peak and is isolated by evaporation of the solvent followed by drying under high vacuum.
  • vial C A third 20 mL scintillation vial (“vial C") is charged with 22.5 mg of 0.1 mmol palladium acetate, 80.7 mg of 0.2 mmol CMPhos, and 1 mL of 1,4-dioxane. 279 ⁇ L of 2.0 mmol triethylamine and 200 ⁇ L of the solution of vial C are pippeted to vial A.
  • vial D A fourth 20 mL scintillation vial (“vial D") is charged with 22.5 mg of 0.1 mmol palladium acetate, 52.5 mg of 0.2 mmol PPh 3 and 1 mL of 1,4-dioxane. 279 ⁇ L of 2.0 mmol triethylamine and 200 ⁇ L of the solution of vial D is pippeted to vial B.
  • Vials A and B are stirred at 80 °C for 17 hours.
  • 1 mL of brine and 2 mL of ethyl acetate are added to each of vials A and B.
  • the organic layers of each vial are separated via pipette.
  • the aqueous layer of each vial is extracted several times with ethyl acetate.
  • the remaining organic layers of each vial are extracted and combined with the respective previously-separated organic layer.
  • Each organic layer is brought to a total weight of 10.00 g by the addition of ethyl acetate.
  • the two reactions are individually worked up by addition of 1 mL brine and 2 mL ethyl acetate and separation of the organic layer via pipette.
  • the aqueous layer is extracted several times with ethyl acetate and the combined organic phases are each brought to a total weight of exactly 10.00 g by addition of ethyl acetate.
  • the remaining 9.00 g organic phase of the CMPhos catalyzed reaction is concentrated and purified by automated flash chromatography (dry loading onto silica loading cartridge, 24g Grace normal phase silica purification cartridge, isocratic hexanes).
  • the product elutes as a single peak and is isolated by evaporation of the solvent followed by drying under high vacuum.
  • a first aromatic compound having a fluorosulfonate substituent may be coupled to a second aromatic compound having a boron-containing substituent.
  • the foregoing reaction can be performed in the presence of water.
  • the foregoing reactions require a lower quantity of catalysts as compared to similar reactions using triflates.
  • the foregoing reactions require a lower quantity of ligands as compared to similar reactions using triflates.
  • the foregoing reactions will not require a dedicated purification step, as is often necessary with similar reactions using triflates.
  • Example 7 One pot conversion of 4-methylphenol to p-tolyl sulfofluoridate in the presence of an inorganic base followed by reaction of p-tolyl sulfofluoridate with phenylboronic acid to yield 4-phenyltoluene as shown in Equation 11.
  • reaction mixtures are then degassed by bubbling N 2 gas for 15 minutes.
  • the vials are taken into a N 2 filled glovebox, and in the following order water (1.50 mL), phenylboronic acid (0.427 g; 3.50 mmol), triphenylphosphine (0.0164 g) and Pd(OAc) 2 (0.0056 g) are added to the vials.
  • the reaction mixtures are heated at 60 °C for 12 hours.
  • the reaction mixtures are cooled to room temperature and each reaction is analyzed by gas chromatography / mass spectroscopy analysis which indicates that reaction A has undergone complete conversion to 4-phenyltoluene and reaction B has undergone >70% conversion to 4-phenyltoluene.
  • Vial A 4-phenyltoluene is isolated as a white solid (0.379 g; 90%) as verified by 1 H NMR.
  • Vial B 4-phenyltoluene is isolated as a white solid (0.270 g; 64%) as verified by 1 H NMR.
  • Equation 13 substituted p-tolyl sulfofluoridate is reacted with phenylboronic acid to yield substituted 4-phenyltoluene as shown in Equation 13.
  • -FG is a generic identifier that designates a functional group which is bonded to the ring at a desired position.
  • the example is conducted as described herein except that the quantities of compounds are modified as follows: 0.5 mol % of NiCl 2 (PCy 3 ) and 1 mol % of PCy3 • HBF 4 .
  • the example is conducted as described herein except that the quantities of compounds are modified as follows: 2 mol % of PCy3 as an additive instead of 2 mol % of PCy 3 •HBF 4 .
  • Example 10 1-(4-hydroxyphenyl)ethanone, phenylboronic acid reacted to yield 1-([1,1'-biphenyl]-4-yl)ethanone.
  • Example 11 4-hydroxybenzaldehyde, phenylboronic acid reacted to yield [1,1'-biphenyl]-4-carbaldehyde.
  • Example 12 4-methylphenol, phenylboronic acid reacted to yield 4-methyl-1,1'-biphenyl.
  • Example 13 Substituted p-tolyl sulfofluoridate, phenylboronic acid reacted to yield substituted biaryl compound.
  • Equation 13 substituted p-tolyl sulfofluoridate is reacted with phenylboronic acid to yield substituted biaryl compound as shown in Equation 13.
  • -FG is a generic identifier that designates a functional group which is bonded to the ring at a desired position.
  • Example 14 Substituted p-tolyl sulfofluoridate, phenylboronic acid reacted to yield substituted 4-phenyltoluene.
  • substituted p-tolyl is first treated with sulfuryl fluoride and is second reacted with phenylboronic acid in a one-pot reaction scheme to yield the product identified in Table 9 as shown in Equation 18.
  • -FG is a generic identifier that designates a functional group which is bonded to the ring at a desired position.
  • triphenylphosphine (0.50 ML of 0.125 M 1,4-dioxane solution); and Pd(OAc) 2 (0.50 mL of 0.05 M acetonitrile solution).
  • the reaction mixture of each vial is stirred for 12 hours at 60 °C.
  • the reaction mixture of each vial is cooled to room temperature and is impregnated on silica gel and the product identified in Table 9 is the isolated yield is calculated using column chromatography and recorded in Table 9.
  • Example 15 p-tolyl sulfofluoridate, phenylboronic acid reacted to yield 4-phenyltoluene.
  • Example 16 p-tolyl sulfofluoridate, phenylboronic acid pinacol ester reacted to yield 4-phenyltoluene.
  • Example 17 p-tolyl sulfofluoridate, potassium phenyltrifluoroborate reacted to yield 4-phenyltoluene.

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Claims (17)

  1. Une méthode de couplage d'un premier composé aromatique à un deuxième composé aromatique, la méthode comprenant :
    le fait de fournir le premier composé aromatique ayant un substituant fluorosulfonate ;
    le fait de fournir le deuxième composé aromatique ayant un substituant contenant du bore ; et
    le fait de faire réagir le premier composé aromatique et le deuxième composé aromatique dans un mélange réactionnel, le mélange réactionnel incluant un catalyseur ayant au moins un atome du groupe 10, le mélange réactionnel étant dans des conditions efficaces pour coupler le premier composé aromatique au deuxième composé aromatique
    dans laquelle
    - les premier et deuxième composés aromatiques sont le sulfofluoridate de p-tolyle et l'acide phénylboronique respectivement, lesquels sont amenés à réagir pour donner du 4-phényltoluène, ou
    - les premier et deuxième composés aromatiques sont le sulfofluoridate de p-tolyle et l'acide tolylboronique respectivement, lesquels sont amenés à réagir pour donner du 4,4'-diméthyl-1,1'-biphényle, ou
    - les premier et deuxième composés aromatiques sont le sulfurofluoridate de 4-(trifluorométhyl)phényle et l'acide phénylboronique respectivement, lesquels sont amenés à réagir pour donner du 4-trifluorométhyl-1,1'-biphényle, ou
    - les premier et deuxième composés aromatiques sont le sulfurofluoridate de 4-(trifluorométhyl)phényle et l'acide tolylboronique respectivement, lesquels sont amenés à réagir pour donner du 4-phényltoluène, ou
    - les premier et deuxième composés aromatiques sont le sulfurofluoridate de pyridin-3-yle et l'acide phénylboronique respectivement, lesquels sont amenés à réagir pour donner de la 3-(p-tolyl)pyridine, ou
    - les premier et deuxième composés aromatiques sont le sulfurofluoridate de pyridin-3-yle et l'acide p-tolylboronique respectivement, lesquels sont amenés à réagir pour donner de la 3-(p-tolyl)pyridine, ou
    - les premier et deuxième composés aromatiques sont le sulfofluoridate de p-tolyle substitué et l'acide phénylboronique respectivement, lesquels sont amenés à réagir pour donner du 4-phényltoluène substitué, le fluorosulfonate substitué et le 4-phényltoluène substitué étant sélectionnés dans le groupe constitué du fluorosulfonate substitué et des 4-phényltoluènes substitués suivants : fluorosulfonate substitué 4-phényltoluènes substitués
    Figure imgb0136
    Figure imgb0137
    Figure imgb0138
    Figure imgb0139
    Figure imgb0140
    Figure imgb0141
    Figure imgb0142
    Figure imgb0143
    Figure imgb0144
    Figure imgb0145
    Figure imgb0146
    Figure imgb0147
    Figure imgb0148
    Figure imgb0149
    Figure imgb0150
    Figure imgb0151
    Figure imgb0152
    Figure imgb0153
    Figure imgb0154
    Figure imgb0155
    Figure imgb0156
    Figure imgb0157
    , ou
    - les premier et deuxième composés aromatiques sont le sulfofluoridate de p-tolyle substitué et l'acide phénylboronique respectivement, lesquels sont amenés à réagir pour donner un composé biaryle substitué, le fluorosulfonate substitué et le composé biaryle substitué étant sélectionnés dans le groupe constitué des fluorosulfonates substitués et des composés biaryle substitués suivants : fluorosulfonates substitués composés biaryle substitués
    Figure imgb0158
    Figure imgb0159
    Figure imgb0160
    Figure imgb0161
    Figure imgb0162
    Figure imgb0163
    Figure imgb0164
    Figure imgb0165
    Figure imgb0166
    Figure imgb0167
    dans lesquels R = SO2F, ou
    - les premier et deuxième composés aromatiques sont le sulfofluoridate de p-tolyle et l'ester pinacolique d'acide phénylboronique respectivement, lesquels sont amenés à réagir pour donner du 4-phényltoluène, ou
    - les premier et deuxième composés aromatiques sont le sulfofluoridate de p-tolyle et le phényltrifluoroborate de potassium respectivement, lesquels sont amenés à réagir pour donner du 4-phényltoluène.
  2. La méthode de la revendication 1, dans laquelle le mélange réactionnel inclut en outre un ligand, et une base.
  3. La méthode de n'importe laquelle des revendications 1 à 2, dans laquelle soit le premier composé aromatique, soit le deuxième composé aromatique est un hétéroaryle.
  4. La méthode de n'importe laquelle des revendications 1 à 3 dans laquelle le catalyseur est un catalyseur au palladium ou un catalyseur au nickel.
  5. La méthode de la revendication 4, dans laquelle le catalyseur est engendré in-situ à partir d'un précatalyseur au palladium, le précatalyseur au palladium est sélectionné dans le groupe constitué : de l'acétate de Palladium(II), du chlorure de Palladium(II), du Dichlorobis(acétonitrile)palladium(II), du Dichlorobis(benzonitrile)palladium(II), d'un dimère de chlorure d'Allylpalladium, de l'acétylacétonate de Palladium(II), du bromure de Palladium(II), du Bis(dibenzylidèneacétone)palladium(0), d'un dimère de chlorure de Bis(2-méthylallyl)palladium, d'une dimère de chlorure de Crotylpalladium, du Dichloro(1,5-cyclooctadiène)palladium(II), du Dichloro(norbornadiène)palladium(II), du trifluoroacétate de Palladium(II), du benzoate de Palladium(II), du triméthylacétate de Palladium(II), de l'oxyde de Palladium(II), du cyanure de Palladium(II), du Tris(dibenzylidèneacétone)dipalladium(0), de l'hexafluoroacétylacétonate de Palladium(II), du cis-Dichloro(N,N,N',N'-tétraméthyléthylène diamine)palladium(II), du Cyclopentadiényl[(1,2,3-n)-1-phényl-2-propényl]palladium(II), du dichlorure de [1,3-Bis(2,6-Diisopropylphényl)imidazol-2-ylidène](3-chloropyridyl)palladium(II), du dichlorure de (1,3-Bis(2,6-diisopropylphényl)imidazolidène)(3-chloropyridyl)palladium(II), et d'un mélange de deux de ceux-ci ou plus.
  6. La méthode de la revendication 4, dans laquelle le catalyseur est engendré in-situ à partir d'un précatalyseur au nickel, le précatalyseur au nickel est sélectionné dans le groupe constitué : de l'acétate de nickel(II), du chlorure de nickel(II), du dichlorure de Bis(triphénylphosphine)nickel(II), du dichlorure de Bis(tricyclohexylphosphine)nickel(II), du [1,1'-Bis(diphénylphosphino)ferrocène]dichloronickel(II), du Dichloro[1,2-bis(diéthylphosphino)éthane]nickel(II), du Chloro(1-naphtyl)bis(triphénylphosphine)nickel(II), du chlorure de 1,3-Bis(2,6-diisopropylphényl)imidazolium, du Bis(1,5-cyclooctadiène)nickel(0), d'un complexe d'éther diméthylique d'éthylène glycol et de chlorure de Nickel(II), du [1,3-Bis(diphénylphosphino)propane]dichloronickel(II), du [1,2-Bis(diphénylphosphino)éthane]dichloronickel(II), du Bis(tricyclohexylphosphine)nickel(0).
  7. La méthode de n'importe laquelle des revendications 2 à 6 dans laquelle le ligand inclut un ou plusieurs éléments parmi un ligand phosphine, un ligand carbène, un ligand à base d'amine, un ligand à base d'aminophosphine.
  8. La méthode de n'importe laquelle des revendications 2 à 7, dans laquelle la base est un sel de carbonate, un sel de phosphate, un sel d'acétate ou un sel d'acide carboxylique.
  9. La méthode de n'importe laquelle des revendications 2 à 8, dans laquelle la base est sélectionnée dans le groupe constitué du carbonate de lithium, du carbonate de sodium, du carbonate de potassium, du carbonate de rubidium, du carbonate de césium, du carbonate d'ammonium, de carbonates d'ammonium substitués, de carbonates d'hydrogène, du phosphate de lithium, du phosphate de sodium, du phosphate de potassium, du phosphate de rubidium, du phosphate de césium, du phosphate d'ammonium, de phosphates d'ammonium substitués, de phosphates d'hydrogène, de l'acétate de lithium, de l'acétate de sodium, de l'acétate de potassium, de l'acétate de rubidium, de l'acétate de césium, de l'acétate d'ammonium, d'acétates d'ammonium substitués, de sels de formiate, de sels de fluoroacétate, d'anions propionate avec du lithium, du sodium, du potassium, du rubidium, du césium, de l'ammonium, et de cations ammonium substitués, de l'hydroxyde de lithium, de l'hydroxyde de sodium, de l'hydroxyde de potassium, du dihydroxyde de magnésium, du dihydroxyde de calcium, du dihydroxyde de strontium, et du dihydroxyde de baryum, du trihydroxyde d'aluminium, du trihydroxyde de gallium, du trihydroxyde d'indium, du trihydroxyde de thallium, de la triéthylamine, de la N,N-diisopropyléthylamine, du 1,4-diazabicyclo[2.2.2]octane, du 1,5-Diazabicyclo[4.3.0] non-5-ène, du 1,8-Diazabicyclo[5.4.0]undéc-7-ène, de sels de lithium, de sodium, et de potassium de bis(triméthylsilyl)amide, de sels de lithium, de sodium, et de potassium de t-butoxyde, du 1,8-bis(diméthylamino)naphtalène, de la pyridine, de la morpholine, de la 2,6-lutidine, de la triéthylamine, de la N,N-Dicyclohexylméthylamine, de la diisopropylamine, du fluorure de sodium, du fluorure de potassium, du fluorure de césium, du fluorure d'argent, du fluorure de tétrabutylammonium, du fluorure d'ammonium, du fluorure de triéthylammonium et d'un mélange de deux de ceux-ci ou plus.
  10. La méthode de n'importe laquelle des revendications 1 à 9, dans laquelle le mélange réactionnel inclut un solvant, le solvant étant sélectionné dans le groupe constitué du toluène, de xylènes (ortho-xylène, méta-xylène, para-xylène ou mélanges de ceux-ci), du benzène, de l'eau, du méthanol, de l'éthanol, du 1-propanol, du 2-propanol, du n-butanol, du 2-butanol, du pentanol, de l'hexanol, de l'alcool tert-butylique, de l'alcool tert-amylique, de l'éthylène glycol, du 1,2-propanediol, du 1,3-propanediol, du glycérol, de la N-méthyl-2- pyrrolidone, de l'acétonitrile, du N,N-diméthylformamide, de l'acétate de méthyle, de l'acétate d'éthyle, de l'acétate de propyle, de l'acétate d'isopropyle, de la triacétine, de l'acétone, de la méthyléthyl cétone, et de solvants éthérés, tels que le 1,4-dioxane, le tétrahydrofurane, le 2-méthyltétrahydrofurane, l'éther diéthylique, l'éther cyclopénylméthylique, l'éther 2-butyléthylique, le diméthoxyéthane, et le polyéthylène glycol.
  11. La méthode de n'importe laquelle des revendications 1 à 10, dans laquelle le substituant contenant du bore est de la formule -BF3 -M+ où M+ est un cation métallique alcalin ou un ion ammonium non substitué.
  12. La méthode de n'importe laquelle des revendications 1 à 11, dans laquelle le substituant contenant du bore est sous la forme :
    Figure imgb0168
     où R3 et R4 sont chacun un alkyle en C1-18 ou un aryle en C6-18, H, B, ou sont liés ensemble par covalence pour former un cycle, et A2 représente un deuxième composé aromatique.
  13. Une méthode de couplage d'un premier composé aromatique à un deuxième composé aromatique, la méthode comprenant :
    le fait de fournir le premier composé aromatique ayant un substituant hydroxyle ;
    le fait de fournir du fluorure de sulfuryle en présence d'une base ;
    le fait de faire réagir le premier composé aromatique et le fluorure de sulfuryle dans un mélange réactionnel, le mélange réactionnel étant dans des conditions efficaces pour coupler l'atome de soufre du fluorure de sulfuryle à l'oxygène du groupe hydroxyle ;
    le fait de fournir au mélange réactionnel le deuxième composé aromatique ayant un substituant contenant du bore ;
    le fait de fournir au mélange réactionnel un catalyseur ayant au moins un atome du groupe 10 ; et
    le fait de faire réagir le premier composé aromatique et le deuxième composé aromatique dans le mélange réactionnel, le mélange réactionnel étant dans des conditions efficaces pour coupler le premier composé aromatique au deuxième composé aromatique, et dans laquelle la réaction est effectuée en tant que réaction monotope.
  14. La méthode de la revendication 13, la base comprenant une base inorganique.
  15. La méthode de la revendication 14, la base comprenant une base amine.
  16. La méthode de n'importe laquelle des revendications 13 à 15, le catalyseur comprenant un catalyseur à base de nickel.
  17. Une méthode de couplage d'un premier composé aromatique à un deuxième composé aromatique, la méthode comprenant :
    le fait de fournir le premier composé aromatique ayant un substituant fluorosulfonate ;
    le fait de fournir le deuxième composé aromatique ayant un substituant contenant du bore ; et
    le fait de faire réagir le premier composé aromatique et le deuxième composé aromatique dans un mélange réactionnel, le mélange réactionnel incluant un catalyseur ayant au moins un atome du groupe 10, le mélange réactionnel étant dans des conditions efficaces pour coupler le premier composé aromatique au deuxième composé aromatique
    dans laquelle le catalyseur est un catalyseur à base de nickel.
EP15716307.2A 2014-03-28 2015-03-27 Procédé de couplage d'un premier composé aromatique à un second composé aromatique Not-in-force EP3122707B1 (fr)

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CN107286061A (zh) * 2017-06-09 2017-10-24 武汉理工大学 一种酚类化合物脱氧还原方法
CN107935802A (zh) * 2017-12-04 2018-04-20 遵义医学院 一种以芳基磺酰氟为原料制备联芳类化合物的方法
CN108586262A (zh) * 2018-01-19 2018-09-28 遵义医学院 一种基于一锅法的不对称三联苯类化合物的合成方法
CN108218717B (zh) * 2018-01-19 2020-01-07 遵义医科大学 一种利用溴代芳基磺酰氟制备不对称三联苯类化合物的方法
CN111362805A (zh) * 2020-03-16 2020-07-03 遵义医科大学 一种以苯酚为原料合成联苯类化合物的方法
CN111410599A (zh) * 2020-03-21 2020-07-14 浙江华贝药业有限责任公司 一种化合物的纯化方法
JP7591748B2 (ja) * 2020-11-16 2024-11-29 国立研究開発法人産業技術総合研究所 有機生成物の製造方法
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US20170174582A1 (en) 2017-06-22
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EP3122707A1 (fr) 2017-02-01
WO2015148931A1 (fr) 2015-10-01
JP2017516746A (ja) 2017-06-22

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